Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Native resistance to conventional chemotherapy remains an important cause of treatment failure in the adult acute leukemias. Delineation of cellular mechanisms of drug resistance therefore represents a prerequisite to the development of more effective treatment strategies. The multidrug resistance (MDR) phenotype represents one such mechanism of resistance with direct clinical relevance. This phenotype occurs normally in certain mammalian tissues, and is detectable in tumor cell lines selected for resistance to naturally occurring antineoplastics. The mdr1 gene or its glycoprotein product, P-glycoprotein, is detected with high frequency in secondary acute myeloid leukemia (AML) and poor-risk subsets of acute lymphoblastic leukemia. In prospective studies in AML, MDR overexpression is an independent determinant of response to treatment and overall survival with conventional-dose induction regimens. Investigations of mdr1 regulation in normal hematopoietic elements has shown a pattern which corresponds to its regulation in acute leukemia, explaining the linkage of mdr1 to specific cellular phenotypes. Therapeutic trials are now in progress to test the ability of various MDR-reversal agents to restore chemotherapy sensitivity in high-risk acute leukemias.
Leuk Lymphoma 1992 Sep
PMID:Multidrug resistance in acute leukemia: a conserved physiologic function. 128 51

Two cell lines resistant to 0.1 microM vincristine (VCR) and 2.0 microM adriamycin (ADR), respectively, (designated HOB1/VCR0.1 and HOB1/ADR2.0) were established from a human immunoblastic B lymphoma cell line. These cell lines showed the typical MDR phenotype with overexpression of P-glycoprotein and decreased [3H]VCR accumulation. The retention amounts of intracellular [3H]VCR in these two cell lines could be augmented by verapamil. However, in spite of the overproduction of P-glycoprotein, both HOB1/VCR1.0 and HOB1/ADR2.0 cells did not exhibit decreased accumulation of intracellular [14C]ADR. And the retention of [14C]ADR was not affected by verapamil. Our data support that P-glycoprotein is a drug transporter more important for the development of drug resistance to VCR than to ADR.
 ...
PMID:Multidrug resistant HOB1 lymphoma cells express P-glycoprotein that does not play the major role in the development of drug resistance to adriamycin. 136 Feb 9

Sequential evaluation of P-glycoprotein expression was performed in 29 patients with acute nonlymphoblastic leukemia using immunocytochemistry with the C219 antibody. At diagnosis, 32% of the patients exhibited more than 5% of the P-gp(+) leukemic cells. Under chemotherapy, 62% of the patients eventually expressed a subset of P-gp positive leukemic cells. After conventional doses of cytosine-arabinoside (Ara-C) and daunorubicin or mitoxantrone, positive P-gp cells were noted in 65% of the cases. This percentage was significantly higher (p = 0.002) than the proportion of positive cases (15%) observed after regimens containing either intermediate doses of Ara-C or cyclosporine A, a P-gp modulator.
Leuk Lymphoma 1992 Nov
PMID:Multidrug resistance (MDR) gene expression in acute non lymphoblastic leukemia: sequential analysis. 136 83

A human diffuse large cell lymphoma line (WSU-DLCL) expressing multidrug resistance (MDR) was established from a patient with primary chemotherapy-resistant disease. This cell line has the same phenotypic features as malignant cells from the patient. The established cell line has features of a mature B-cell neoplasm with no evidence for commitment to other lineages. WSU-DLCL grows in suspension forming relatively large clumps of cells with a doubling time of 20 hours. By light microscopic examination, the cells are very large with primitive lymphoid features, have a large amount of cytoplasm containing numerous vacuoles and an irregular outline. Immunophenotypic characterization by monoclonal antibodies and flow cytometric analysis showed a monoclonal IgM kappa B-cell phenotype with high expression of the multidrug-resistant P-glycoprotein compared with either normal peripheral blood lymphocytes or cells of the REH cell line. The cells were negative for T-cell and myeloid/monocyte antigens as well as Epstein-Barr virus nuclear antigen (EBNA). In addition, the cell line expressed high levels of MDR RNA. DNA histogram generated by flow cytometry indicated a DNA index of 1.83. Cytogenetic analysis confirmed hypertriploidy and showed complex chromosomal abnormalities including 14q+. This cell line should be a valuable tool to study the role of the MDR gene in the primary resistance of lymphomas to chemotherapy and to facilitate therapeutic investigations.
 ...
PMID:A human B-cell lymphoma line with a de novo multidrug resistance phenotype. 154 Aug 84

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.
 ...
PMID:P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. 167 Jun 42

Flow cytometric detection of surface P-glycoprotein, a multidrug-resistant gene product, with a monoclonal antibody, MRK 16, was performed on cells obtained from 18 children with leukaemia and lymphoma. Of 18 patients examined, 1 with malignant lymphoma at relapse showed a significant increase in P-glycoprotein-positive cells and a strong resistance to chemotherapy. Overexpression of P-glycoprotein in a case with B-cell type malignant lymphoma was confirmed by immuno-precipitation and Northern hybridization analysis. The present study suggests that an increased expression of surface P-glycoprotein might be involved in multidrug resistance at least in a certain case of childhood leukaemia and lymphoma.
 ...
PMID:Detection of multidrug-resistant protein, P-glycoprotein in childhood leukaemia and lymphoma. 167 13

Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.
 ...
PMID:Multidrug resistance gene (MDR1) expression in human brain tumors. 168 28

To characterize the membrane changes related to adriamycin (ADM) resistance in tumor cells, we have developed monoclonal antibodies against an ADM-resistant subline of human myelogenous leukemia K562 (K562/ADM), and reported the overexpression of P-glycoprotein and 85-kDa protein as determined by the antibodies. In the present study, we have established a monoclonal antibody, MRK18, with higher reactivity to K562/ADM than to K562. MRK18 also showed higher reactivity to other human ADM-resistant lines, 2780AD and Hattori/ADM, than the corresponding parental lines. MRK18 also reacted to human breast cancer MCF-7 and human T-lymphoma CCRF-CEM which have never been exposed to anticancer agents in culture. MRK18 recognized a 300-kDa membrane protein of K562/ADM and MCF-7 and inhibited the growth of these cell lines in culture. These results indicate an induction of the 300-kDa protein during the development of ADM resistance.
 ...
PMID:Detection of 300-kilodalton membrane protein in adriamycin-resistant human tumor cells by a monoclonal antibody MRK18. 197 22

A number of recent studies have implied that a relationship exists between cellular sensitivities to tumor necrosis factor (TNF) and expression of the classic multidrug resistance (MDR) phenotype. However, different conclusions have been reported concerning whether TNF sensitivity is positively or negatively correlated with MDR (Hong, W.-S.; Sijo, N.; Sasaki, Y.; Shinkai, T.; Eguchi, K.; Sakurai, M.; Takamashi, H.; Nakano, H.; Nakagawa, K.; Twentyman, P. R. Jpn. J. Can. Res. (Gann) 78:1274-1280; 1987 and Dollbaum, C.; Creasey, A. A.; Dairkee, S. H.; Hiller, A. J.; Rudolph, A. R.; Lin, L.; Vitt, C.; Smith, H. S. Proc. Natl. Acad. Sci. USA 85:4740-4755; 1988). An apparent relationship of TNF sensitivity to P-glycoprotein (P-170gp) mediated MDR was investigated in EL4 murine T-lymphoma cell lines sensitive and resistant to Adriamycin (ADM). No consistent association was found between MDR and TNF responses when the lines were subcloned. Whereas the MDR phenotype of subclones (as assessed by ADM resistance and P-170gp expression) reflected that of the cell line from which they were derived, the TNF sensitivity of subclones varied widely. Also consistent with independence of P-170gp mediated MDR and TNF response, the P388/ADM cell line (exhibiting P-170gp mediated MDR) remained as resistant to TNF as the P388 parental line. In addition, no evidence was found of modified recognition of MDR EL4 cell lines by host defense effector cells, and gamma-interferon failed to enhance the susceptibility of either parental or MDR cell line to TNF. These results may be of value in considering therapeutic studies using the ADM/TNF combination treatment.
 ...
PMID:The relationship between multidrug resistance and tumor necrosis factor resistance in an EL4 cell line model. 197 58

This paper describes the cellular and tissue distribution of P-glycoprotein (P-GP) (mdr1 gene product), the role of P-GP in vivo and immunodiagnosis of multi-drug-resistant cancers. We mainly used MRK 16 monoclonal antibody (MAb) reactive with P-GP. P-GP was found to be expressed very strongly in the adrenal cortex of adults and strongly in the renal tubules of the kidney, capillary blood vessels of the brain, and also in placenta. Interestingly, P-GP was not distributed in fetal and neonatal adrenals, and thus may be closely related to adrenal maturation. A high level of P-GP expression was also seen in all cases of functional hormone-producing adrenal tumor, one case of insulinoma, two cases of untreated colonic cancer, one case each of untreated lung cancer, gastric cancer and breast cancer, six cases of renal cell carcinoma and 17 cases of bladder cancer. Using flow cytometry and immunocytochemistry, we investigated the reactivity of MRK 16 MAb with peripheral human mononuclear cells (mainly blastic cells and lymphocytes) from 31 patients with leukemia or malignant lymphoma. Reactivity with MRK 16 MAb was observed in five cases. Some cases reflected the prior administration of adriamycin, vincristine and VP-16, which are known to induce P-GP expression. P-GP-MRK 16-protein A-Sepharose complex derived from human adrenal possessed marked ATPase activity. These data suggest that P-GP may play a physiological role in the human adrenal. Finally, diagnostic criteria of multi-drug-resistant cancers are presented.
 ...
PMID:Expression and functions of P-glycoprotein (mdr1 gene product) in normal and malignant tissues. 197 61


1 2 3 4 5 6 7 8 9 10 Next >>